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Objective: CD28 and inducible T cell costimulator (ICOS) appear to have nonredundant roles in T cell activation and adaptive immunity. We undertook this study to characterize in vitro and in vivo the therapeutic potential of acazicolcept (ALPN-101), an Fc fusion protein of a human variant ICOS ligand (ICOSL) domain designed to inhibit both CD28 and ICOS costimulation, in inflammatory arthritis., Methods: Acazicolcept was compared in vitro with inhibitors of either the CD28 or ICOS pathways (abatacept and belatacept [CTLA-4Ig], prezalumab [anti-ICOSL monoclonal antibody]) in receptor binding and signaling assays, and in a collagen-induced arthritis (CIA) model. Acazicolcept was also compared in cytokine and gene expression assays of peripheral blood mononuclear cells (PBMCs) from healthy donors or rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients stimulated with artificial antigen-presenting cells (APCs) expressing CD28 and ICOS ligands*., Results: Acazicolcept bound CD28 and ICOS, prevented ligand binding, and inhibited human T cell functional interactions, matching or exceeding the activity of CD28 or ICOS costimulatory single-pathway inhibitors tested individually or in combination. Acazicolcept administration significantly reduced disease in the CIA model and more potently than abatacept. Acazicolcept also inhibited proinflammatory cytokine production from stimulated PBMCs in cocultures with artificial APCs and demonstrated unique effects on gene expression distinct from those induced by abatacept, prezalumab, or a combination of both., Conclusion: Both CD28 and ICOS signaling play critical roles in inflammatory arthritis. Therapeutic agents such as acazicolcept that coinhibit both ICOS and CD28 signaling may mitigate inflammation and/or disease progression in RA and PsA more effectively than inhibitors of either pathway alone., (© 2023 American College of Rheumatology.)

Radiation therapy induces immunogenic cell death in cancer cells, whereby released endogenous adjuvants are sensed by immune cells to direct adaptive immune responses. TLRs expressed on several immune subtypes recognize innate adjuvants to direct downstream inflammatory responses in part via the adapter protein MyD88. We generated Myd88 conditional knockout mice to interrogate its contribution to the immune response to radiation therapy in distinct immune populations in pancreatic cancer. Surprisingly, Myd88 deletion in Itgax (CD11c)-expressing dendritic cells had little discernable effects on response to RT in pancreatic cancer and elicited normal T cell responses using a prime/boost vaccination strategy. Myd88 deletion in Lck-expressing T cells resulted in similar or worsened responses to radiation therapy compared to wild-type mice and lacked antigen-specific CD8 + T cell responses from vaccination, similar to observations in Myd88 -/- mice. Lyz2-specific loss of Myd88 in myeloid populations rendered tumors more susceptible to radiation therapy and elicited normal CD8 + T cell responses to vaccination. scRNAseq in Lyz2-Cre/Myd88 fl/fl mice revealed gene signatures in macrophages and monocytes indicative of enhanced type I and II interferon responses, and improved responses to RT were dependent on CD8 + T cells and IFNAR1. Together, these data implicate MyD88 signaling in myeloid cells as a critical source of immunosuppression that hinders adaptive immune tumor control following radiation therapy., (© 2023. The Author(s).)

Radiation therapy generates extensive cancer cell death capable of promoting tumor-specific immunity. Within the tumor, conventional dendritic cells (cDCs) are known to carry tumor-associated antigens to the draining lymph node (TdLN) where they initiate T-cell priming. How radiation influences cDC migration is poorly understood. Here, we show that immunological efficacy of radiation therapy is dependent on cDC migration in radioimmunogenic tumors. Using photoconvertible mice, we demonstrate that radiation impairs cDC migration to the TdLN in poorly radioimmunogenic tumors. Comparative transcriptional analysis revealed that cDCs in radioimmunogenic tumors express genes associated with activation of endogenous adjuvant signaling pathways when compared with poorly radioimmunogenic tumors. Moreover, an exogenous adjuvant combined with radiation increased the number of migrating cDCs in these poorly radioimmunogenic tumors. Taken together, our data demonstrate that cDC migration play a critical role in the response to radiation therapy., (© 2022 Blair et al.)

Surgical resection of head and neck squamous-cell carcinoma (HNSCC) is associated with high rates of local and distant recurrence, partially mitigated by adjuvant therapy. A pre-existing immune response in the patient's tumor is associated with better outcomes following treatment with conventional therapies, but improved options are needed for patients with poor anti-tumor immunity. We hypothesized that local delivery of tumor antigen-specific T-cells into the resection cavity following surgery would direct T-cells to residual antigens in the margins and draining lymphatics and present a platform for T-cell-targeted immunotherapy. We loaded T-cells into a biomaterial that conformed to the resection cavity and demonstrated that it could release T-cells that retained their functional activity in-vitro , and in a HNSCC model in-vivo . Locally delivered T-cells loaded in a biomaterial were equivalent in control of established tumors to intravenous adoptive T-cell transfer, and resulted in the systemic circulation of tumor antigen-specific T-cells as well as local accumulation in the tumor. We demonstrate that adjuvant therapy with anti-PD1 following surgical resection was ineffective unless combined with local delivery of T-cells. These data demonstrate that local delivery of tumor-specific T-cells is an efficient option to convert tumors that are unresponsive to checkpoint inhibitors to permit tumor cures., Competing Interests: CONFLICTS OF INTEREST MJG and MRC receive research funding from Bristol Myers-Squibb, Jounce, and Mavupharma that is unrelated to the content of this manuscript. The remaining authors declare no competing interests. Funders had no input in the content of the manuscript., (Copyright: © 2021 Sharon et al.)

Analysis of tumor infiltration using conventional methods reveals a snapshot view of lymphocyte interactions with the tumor environment. However, lymphocytes have the unique capacity for continued recirculation, exploring varied tissues for the presence of cognate antigens according to inflammatory triggers and chemokine gradients. We discuss the role of the inflammatory and cellular makeup of the tumor environment, as well as antigen expressed by cancer cells or cross-presented by stromal antigen presenting cells, on recirculation kinetics of T cells. We aim to discuss how current cancer therapies may manipulate lymphocyte recirculation versus retention to impact lymphocyte exclusion in the tumor., Competing Interests: MG and MC receive research funding from Bristol Myers-Squibb, Jounce, and Mavupharma that is unrelated to the content of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Blair, Alice, Zebertavage, Crittenden and Gough.)

In the cancer literature tumors are inconsistently labeled as 'immunogenic', and experimental results are occasionally dismissed since they are only tested in known 'responsive' tumor models. The definition of immunogenicity has moved from its classical definition based on the rejection of secondary tumors to a more nebulous definition based on immune infiltrates and response to immunotherapy interventions. This review discusses the basis behind tumor immunogenicity and the variation between tumor models, then moves to discuss how these principles apply to the response to radiation therapy. In this way we can identify radioimmunogenic tumor models that are particularly responsive to immunotherapy only when combined with radiation, and identify the interventions that can convert unresponsive tumors so that they can also respond to these treatments., Competing Interests: MG and MC received research funding from Bristol Myers-Squibb, Jounce, and Mavupharma that is unrelated to the content of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Medler, Blair, Crittenden and Gough.)

The CD200-CD200R pathway is involved in inhibition of immune responses, and the importance of this pathway to infectious disease is highlighted by the fact that viral CD200 (vCD200) molecules have been found to be encoded by several DNA viruses, including the human gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), and the closely related rhesus macaque rhadinovirus (RRV). KSHV vCD200 is the most extensively studied vCD200 molecule, however, the only herpesvirus vCD200 molecule to be examined in vivo is that encoded by RRV. Our prior studies have demonstrated that RRV vCD200 is a functional CD200 homologue that is capable of affecting immune responses in vivo , and further, that RRV can express a secreted form of vCD200 (vCD200-Sec) during infection. Despite this information, RRV vCD200 has not been examined specifically for effects on RM CD200R signaling, and the functionality of vCD200-Sec has not been examined in any context. Thus, we developed an in vitro model system in which B cells expressing vCD200 were utilized to assess the effects of this molecule on the regulation of myeloid cells expressing RM CD200R, mimicking interactions that are predicted to occur in vivo Our findings suggest that RRV vCD200 can bind and induce functional signals through RM CD200R, while vCD200-Sec represents a non-functional protein incapable of affecting CD200R signaling. We also provide the first demonstration of the function of RM CD200, which appears to possess more robust signaling capabilities than RRV vCD200, and also show that KSHV vCD200 does not efficiently induce signaling via RM CD200R. IMPORTANCE Viral CD200 homologues are encoded by KSHV and the closely related RRV. Though RRV vCD200 has been examined, questions still exist in regard to the ability of this molecule to induce signaling via rhesus macaque CD200R, as well as the potential function of a secreted form of vCD200. Further, all previous in vitro studies of RRV vCD200 have utilized an Fc fusion protein to examine functionality, which does not replicate the structural properties of the membrane-associated form of vCD200 that is naturally produced during RRV infection. In this study, we demonstrate for the first time that membrane-expressed RRV vCD200 is capable of inducing signal transduction via RM CD200R, while the secreted form of vCD200 appears to be non-functional. Further, we also demonstrate that RM CD200 induces signaling via RM CD200R, and is more robust than RRV vCD200, while KSHV vCD200 does not appear to induce efficient signaling via RM CD200R., (Copyright © 2020 American Society for Microbiology.)

Purpose: The role of MerTK, a member of the Tyro3-Axl-MerTK family of receptor tyrosine kinase, in the immune response to radiation therapy (RT) is unclear. We investigated immune-mediated tumor control after RT in murine models of colorectal and pancreatic adenocarcinoma using MerTK wild-type and knock-out hosts and whether inhibition of MerTK signaling with warfarin could replicate MerTK knock-out phenotypes., Methods and Materials: Wild-type and MerTK -/- BALB/c mice were grafted in the flanks with CT26 tumors and treated with computed tomography guided RT. The role of macrophages and CD8 T cells in the response to radiation were demonstrated with cell depletion studies. The role of MerTK in priming immune responses after RT alone and with agonist antibodies to the T cell costimulatory molecule OX40 was evaluated in a Panc02-SIY model antigen system. The effect of warfarin therapy on the in-field and abscopal response to RT was demonstrated in murine models of colorectal adenocarcinoma. The association between warfarin and progression-free survival for patients treated with SABR for early-stage non-small cell lung cancer was evaluated in a multi-institutional retrospective study., Results: MerTK -/- hosts had better tumor control after RT compared with wild-type mice in a macrophage and CD8 T cell-dependent manner. MerTK -/- mice showed increased counts of tumor antigen-specific CD8 T cells in the peripheral blood after tumor-directed RT alone and in combination with agonist anti-OX40. Warfarin therapy phenocopied MerTK -/- for single-flank tumors treated with RT and improved abscopal responses for RT combined with anti-CTLA4. Patients on warfarin therapy when treated with SABR for non-small cell lung cancer had higher progression-free survival rates compared with non-warfarin users., Conclusions: MerTK inhibits adaptive immune responses after SABR. Because warfarin inhibits MerTK signaling and phenocopies genetic deletion of MerTK in mice, warfarin therapy may have beneficial effects in combination with SABR and immune therapy in patients with cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Radiation therapy is capable of directing adaptive immune responses against tumors by stimulating the release of endogenous adjuvants and tumor-associated Ags. Within the tumor, conventional type 1 dendritic cells (cDC1s) are uniquely positioned to respond to these signals, uptake exogenous tumor Ags, and migrate to the tumor draining lymph node to initiate cross-priming of tumor-reactive cytotoxic CD8 + T cells. In this study, we report that radiation therapy promotes the activation of intratumoral cDC1s in radioimmunogenic murine tumors, and this process fails to occur in poorly radioimmunogenic murine tumors. In poorly radioimmunogenic tumors, the adjuvant polyinosinic-polycytidylic acid overcomes this failure following radiation and successfully drives intratumoral cDC1 maturation, ultimately resulting in durable tumor cures. Depletion studies revealed that both cDC1 and CD8 + T cells are required for tumor regression following combination therapy. We further demonstrate that treatment with radiation and polyinosinic-polycytidylic acid significantly expands the proportion of proliferating CD8 + T cells in the tumor with enhanced cytolytic potential and requires T cell migration from lymph nodes for therapeutic efficacy. Thus, we conclude that lack of endogenous adjuvant release or active suppression following radiation therapy may limit its efficacy in poorly radioimmunogenic tumors, and coadministration of exogenous adjuvants that promote cDC1 maturation and migration can overcome this limitation to improve tumor control following radiation therapy., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Surgeons have unique in situ access to tumors enabling them to apply immunotherapies to resection margins as a means to prevent local recurrence. Here, we developed a surgical approach to deliver stimulator of interferon genes (STING) ligands to the site of a purposeful partial tumor resection using a gel-based biomaterial. In a range of head and neck squamous cell carcinoma (HNSCC) murine tumor models, we demonstrate that although control-treated tumors recur locally, tumors treated with STING-loaded biomaterials are cured. The mechanism of tumor control required activation of STING and induction of type I IFN in host cells, not cancer cells, and resulted in CD8 T-cell-mediated cure of residual cancer cells. In addition, we used a novel tumor explant assay to screen individual murine and human HNSCC tumor responses to therapies ex vivo We then utilized this information to personalize the biomaterial and immunotherapy applied to previously unresponsive tumors in mice. These data demonstrate that explant assays identify the diversity of tumor-specific responses to STING ligands and establish the utility of the explant assay to personalize immunotherapies according to the local response. Significance: Delivery of immunotherapy directly to resection sites via a gel-based biomaterial prevents locoregional recurrence of head and neck squamous cell carcinoma. Cancer Res; 78(21); 6308-19. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103 + CD39 + tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103 + CD39 + CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103 + CD39 + CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103 + CD39 + CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies.

Japanese macaque encephalomyelitis (JME) is an inflammatory demyelinating disease that occurs spontaneously in a colony of Japanese macaques (JM) at the Oregon National Primate Research Center. Animals with JME display clinical signs resembling multiple sclerosis (MS), and magnetic resonance imaging reveals multiple T2-weighted hyperintensities and gadolinium-enhancing lesions in the central nervous system (CNS). Here we undertook studies to determine if JME possesses features of an immune-mediated disease in the CNS. Comparable to MS, the CNS of animals with JME contain active lesions positive for IL-17, CD4+ T cells with Th1 and Th17 phenotypes, CD8+ T cells, and positive CSF findings., (Copyright © 2015 Elsevier B.V. All rights reserved.)

During the development of experimental autoimmune encephalomyelitis (EAE), the proportion of pathogenic and myelin-specific cells within CNS-infiltrating cytokine-producing Th cells is unknown. Using an IL-17A/IFN-γ double reporter mouse and I-A(b)/myelin oligodendrocyte glycoprotein 38-49 tetramer, we show in this study that IL-17(+)IFN-γ(+) Th cells, which are expanded in the CNS during EAE, are highly enriched in myelin oligodendrocyte glycoprotein-specific T cells. We further demonstrate that IL-23 is essential for the generation and expansion of IFN-γ-producing Th17 cells independently of the Th1-associated transcription factors T-bet, STAT1, and STAT4. Furthermore, Th17 and IL-17(+)IFN-γ(+) Th cells can induce CNS autoimmunity independently of T-bet. Whereas T-bet is crucial for Th1-mediated EAE, it is dispensable for Th17 cell-mediated autoimmunity. Our results suggest the existence of different epigenetic programs that regulate IFN-γ expression in Th1 and Th17 cells.

Rupture of the normal aortic valve after blunt trauma to the chest is seen infrequently. With the ever-increasing incidence of car and motorcycle accidents, this injury should be considered during the initial examination of an accident victim. Any patient without a history of heart disease presenting with heart murmurs after severe blunt trauma to the chest should give rise to the suspicion of aortic valve damage. When the diagnosis is proved, aortic valve expoloration is necessary. Review of the published cases establishes that valve replacement is the treatment of choice.

To ascertain the risk of thromboembolism and anticoagulant-related hemorrhage following mitral valve replacement with bioprostheses, an 8 year retrospective study between two groups of patients was analyzed. Group I included 206 patients undergoing mitral valve replacement with porcine xenograft valves. They were placed on a regimen of long-term oral anticoagulation (greater than 8 weeks, mean 6 months). Follow-up was 524.3 patient-years, mean 30.5 months. There were 24 thromboembolic events (4.6% per patient-year), four of which were fatal. Actuarially, 80.7% +/- 4.3% are free of thromboembolism at 8 years. There were 12 instances of major bleeding episodes, for a linearized incidence of 2.5% per patient-year; two were fatal. Group II included 322 patients undergoing mitral valve replacement with a bovine pericardial valve. They were placed on a program of short-term anticoagulation (6 weeks only). Follow-up was 1,106 patient-years, mean 46.4 months. There were four thromboembolic episodes (none fatal), an incidence of 0.36% per patient-year. Seven bleeding episodes occurred, 0.63% per patient-year; none was fatal. The difference between the groups reached statistical significance (p less than 0.001). The low risk of thromboembolism with the bovine pericardial valve appears to be due to its superior hydraulic characteristics. Use of this valve allows mitral valve replacement without long-term oral anticoagulation and the associated risk of anticoagulant-related hemorrhage.

This report outlines orthoterminal correction in an 8-year-old boy with coexisting d-transposition of the great arteries (d-TGA), subpulmonary stenosis, and a complete form of atrioventricular canal (CAVC). The repair consisted of covering the tricuspid valve and atrial part of the atrioventricular canal with a Dacron patch and inserting a valve-containing conduit between the then isolated right atrium and the pulmonary artery to create a venous outlet. The patient's exercise tolerance has improved remarkably. The arterial oxygen saturation has risen from 86 to 90 per cent. A plea is made to expand the indications for orthoterminal correction to patients in whom the severity of the heart malformation precludes application of well-established methods of surgical repair.

Between February, 1977, and April, 1982, 168 patients underwent aortic valve replacement (AVR) with an Ionescu-Shiley bovine pericardial valve. Concomitant procedures were performed in 71 patients. There were 12 hospital deaths (7.1%). Among patients having AVR only, there were 5 deaths (5.2%). Assessment included valve durability, incidence of thromboembolism, clinical improvement, and patient survival. There was 100% follow-up. Actuarial freedom from intrinsic valve failure at 5 years was 96.3 +/- 3.6%. Intrinsic valve failure occurred only once, 0.3 episodes per 100 patient-years. Four patients had thromboembolic complications. As for clinical status, 99.3% of surviving patients are in New York Heart Association Functional Class I or II, including 79 patients with valve sizes 17, 19, or 21 mm (56%). Among 13 late deaths, 9 were related to the cardiovascular system. Overall patient survival is 84.9 +/- 4.7%. Among the 92 patients with isolated AVR, 87.8 +/- 5.9% are alive at the 5-year follow-up. If the incidence of valve failure is not altered in years to come, the durability of the Ionescu-Shiley bovine pericardial valve will surpass that of previous bioprostheses.

The risk of postoperative thromboembolism (PTE), anticoagulant related hemorrhage (ARH), and the influence of thromboembolic risk factors ( TERF ) were assessed retrospectively in 206 unselected patients undergoing mitral valve replacement (MVR) with porcine xenobioprotheses ( PXBP ). Other aims were to identify the "high-risk" group with respect to PTE and to assess the effectiveness of long-term anticoagulant therapy (AT) in this subset, as well as to elucidate the most adequate method of AT and ascertain if AT is strictly necessary in patients undergoing MVR with PXBP . Patients were divided in two groups: Group I (N = 115) received long-term AT; there were 22 PTE. Group II (N = 91) with only 8 weeks of AT had 2 PTE (P less than 0.01). ARH was the same in both groups. Actuarially , 71.7% of the patients in group I and 96.3% of the patients in group II were free of PTE at 6 years. Long-term AT proved ineffective in preventing PTE and carried a significant incidence of ARH. ARH surpassed PTE (3.5:1) in patients on short-term AT. Patients without TERF have a low incidence of PTE, and AT is not indicated. The "high-risk" group were patients in postoperative atrial fibrillation and left atrial enlargement. One week heparin therapy and 3 months oral AT is suggested for patients with TERF . PXBP for MVR in patients with TERF is significantly thrombogenic. Early operation is advocated to avoid development of TERF that will affect patient outlook after MVR with PXBP due to the significantly increased risks of PTE and (if placed on AT) ARH.